The creation of diverse chemical structures for efficient biological evaluation and drug screening remains of great importance for the discovery of biologically useful molecules. The efficient creation of molecules with drug-like properties that are also novel compositions or chemical structures is critical if investments for improvements in disease management are to be made.
The identification of small organic molecules that affect specific biological functions is an endeavor that impacts both biology and medicine. Such molecules are useful as therapeutic agents and as probes of biological function. The interaction of small molecules with biological targets and their ability to affect specific biological functions, may also serve as candidates for the development of therapeutics.
Because it is difficult to predict which small molecules will interact with a biological target, intense efforts have been directed towards the generation of large numbers, or libraries of small organic compounds with drug-like pharmaceutical properties. These libraries can then be evaluated in sensitive screens to identify active molecules. In many cases, researchers have developed biased libraries, in which all members share a particular characteristic, such as an ability to interact with a particular target ligand, or a characteristic structural feature designed to mimic a particular aspect of a class of natural compounds. For example, a number of libraries have been designed to mimic one or more features of natural peptides. Such peptidomimetic libraries include phthalimido libraries (WO97/22594), thiophene libraries (WO97/40034), benzodiazopene libraries (U.S. Pat. No. 5,288,514) libraries formed by the sequential reaction of dienes (WO96/03424), thiazolidone libraries, libraries of metathiazanones and their derivatives (U.S. Pat. No. 5,549,974), and azatide libraries (WO 97/35199), isonicotinamide based libraries (U.S. Pat. No. 6,448,443).
Recognizing the need for the development of synthetic strategies that produce large numbers of complex molecules, Boger et al. (EP0774 464) have recently developed a solution-phase synthetic strategy for producing a library of compounds based on a functionalizable template core, to which various reagents can be added. However, there remains a need for development of solid-phase strategies, where the more rapid production methods such as split-and-pool strategies can be employed to generate larger, more complex libraries. Additional solution phase strategies would also be valuable.
Each of the libraries described has provided solid synthetic strategies for compounds possessing specific core functionalities, but none achieves the complexity of structures found in natural products, or in other lead compounds prepared through traditional chemical synthetic routes. Complex natural products have been the source of important pharmaceutical products for the treatment of a host of human diseases and medical conditions. The natural products commonly contain several different functionalities and often are rich in stereochemical complexity. Such diversity and complexity are often difficult to achieve if the synthesis is restricted to a specific class of compounds. In other situations there are limitations in the ability to create analogs over a broad range of lipophilicities, reactivities, stereocomplexities, etc.
In addition, exploiting the diversity and structural complexity of chemical structures from natural products remains a significant goal of medicinal chemists and pharmaceutical corporations. The value of agents of natural product plant origin such as the taxanes, camptothecins, vinca alkaloids, ellipticines, podophyllotoxins, mithramycins, steroids, agents from fermentations such as phleomycins, bleomycin, doxorubicin, vancomycin, penicillin, streptomycins, erythromycins, rapamycins, actinomycins, avermectins, phomopsin, cytochalasins, etc., are some examples which have been of importance for the treatment of life-threatening diseases. Rational exploration of analogs, hybrids, substructures, fragments and variants of these and other complex scaffold structures should be of significant utility in the drug discovery and development process. Moreover, application of more efficient methods of creation of novel chemical structures from such sources and others would increase the chemical space and structural diversity that is extremely important for the identification of potential novel therapeutics.
Thus, a need exists for methods of generating complex libraries of novel molecules useful in the generation of therapeutics.